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Proc Natl Acad Sci U S A ; 114(52): 13738-13743, 2017 12 26.
Article in English | MEDLINE | ID: mdl-29229862

ABSTRACT

The microtubule motor kinesin-1 interacts via its cargo-binding domain with both microtubules and organelles, and hence plays an important role in controlling organelle transport and microtubule dynamics. In the absence of cargo, kinesin-1 is found in an autoinhibited conformation. The molecular basis of how cargo engagement affects the balance between kinesin-1's active and inactive conformations and roles in microtubule dynamics and organelle transport is not well understood. Here we describe the discovery of kinesore, a small molecule that in vitro inhibits kinesin-1 interactions with short linear peptide motifs found in organelle-specific cargo adaptors, yet activates kinesin-1's function of controlling microtubule dynamics in cells, demonstrating that these functions are mechanistically coupled. We establish a proof-of-concept that a microtubule motor-cargo interface and associated autoregulatory mechanism can be manipulated using a small molecule, and define a target for the modulation of microtubule dynamics.


Subject(s)
Enzyme Activators , Kinesins , Microtubules , Amino Acid Motifs , Enzyme Activators/chemistry , Enzyme Activators/pharmacology , HeLa Cells , Humans , Kinesins/chemistry , Kinesins/genetics , Kinesins/metabolism , Microtubules/chemistry , Microtubules/genetics , Microtubules/metabolism
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